Waardenburg syndrome type I (WS1, 193500) is a significant cause of congenital deafness in humans. By means of a multipoint linkage analysis (Asher et al. 1991a), one WS1 mutation has been mapped to the chromosomal region 2q37, thus confirming and extending the findings of Foy et al. (1990). Furthermore, these linkage findings appear to confirm a prediction (Asher and Friedman 1990) that the mouse mutation Sp (Splotch) is a good model for some WS1 mutations. The long-range goals of this project are to: (1) clone the WS1 and Sp genes, (2) discover the primary defects caused by WS1 and Sp mutations, and (3) determine the mechanism(s) by which specific WS1 mutations cause deafness. The immediate goal of this research project is to clone the WS1 and Sp genes. This endeavor will be successful because of the following advantages. First, in collaboration with Dr. D. H. Johnson, a human microclone library of the human 2q37 _region was constructed. Second, Dr. Susan Naylor has provided genomic DNA from human/hamster somatic cell hybrid lines which have complementary deletions of portions of the tip of 2q covering the suspected location of WS1. Third, genomic DNA from Sp(r)/+ and +/+ mice will be used to select human microclones that map within the Sp(r) deletion. Fourth, genomic DNA samples from 2,000 interspecific backcross mice are being produced that will allow the construction of a fine-structure genetic map of clones tightly linked to the Sp-locus. Finally, in collaboration with Dr. Edward Wilcox, NIDCD, clones will be tested to determine if they are close enough to the WS1 locus to reveal differences in the physical map caused by a sporadic inversion described by Ishikiriyama et al. (1989). This selection protocol should identify a cDNA clone which detects an altered physical map in sporadic cases of Waardenburg syndrome. These studies should test directly the hypothesis that Sp and WS1 are homologous genes. If this hypothesis is true, the mouse Sp-locus will be a powerful research model to determine the primary defects caused by WS1.